(m-CF3-PhSe)2 counteracts metabolic disturbances and hypothalamic inflammation in a lifestyle rodent model.

An unhealthy lifestyle is associated with metabolic disorders and neuroinflammation. In this study, the efficacy of m-trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] against lifestyle model-related metabolic disturbances and hypothalamic inflammation in young mice was investigated. From postnatal day 25 (PND25) to 66, male Swiss mice were subjected to a lifestyle model, an energy-dense diet (20:20% lard: corn syrup) and sporadic ethanol (3x/week). Ethanol was administrated intragastrically (i.g., 2 g/kg) to mice from PND45 to 60. From PND60 to 66, mice received (m-CF3-PhSe)2 (5 mg/kg/day; i. g). (m-CF3-PhSe)2 reduced relative abdominal adipose tissue weight, hyperglycemia, and dyslipidemia in mice exposed to the lifestyle-induced model. (m-CF3-PhSe)2 normalized hepatic cholesterol and triglyceride levels, and the activity of G-6-Pase increased in lifestyle-exposed mice. (m-CF3-PhSe)2 was effective in modulating hepatic glycogen levels, citrate synthase and hexokinase activities, protein levels of GLUT-2, p-IRS/IRS, p-AKT/AKT, redox homeostasis, and inflammatory profile of mice exposed to a lifestyle model. (m-CF3-PhSe)2 counteracted hypothalamic inflammation and the ghrelin receptor levels in mice exposed to the lifestyle model. (m-CF3-PhSe)2 reversed the decreased levels of GLUT-3, p-IRS/IRS, and the leptin receptor in the hypothalamus of lifestyle-exposed mice. In conclusion, (m-CF3-PhSe)2 counteracted metabolic disturbances and hypothalamic inflammation in young mice exposed to a lifestyle model.

Stereoselective Reduction of Alkynes: Synthesis of 4-Organoselenyl Quinolines.

This study describes the reaction of 2-amino arylalkynyl ketones with organoselenolates to form (Z)-vinyl selenides, which lead to 4-organoselenyl quinolines via an intramolecular condensation. Using the optimized reaction conditions, the generality of this cyclization was studied with various arylalkynyl ketones and diorganyl diselenides. The study of the reaction mechanisms led to the isolation and identification of a vinyl selenide, which was the key intermediate for this cyclization. To expand the structural diversity and to demonstrate the applicability of the 4-organoselenyl quinolines prepared, we studied their application as substrates in the cleavage of the carbon-selenium bond using n-butyllithium followed by the capture of the lithium intermediate by electrophiles and Suzuki and Sonogashira cross-coupling reactions.

In vitro activity of diphenyl diselenide and ebselen alone and in combination with antifungal agents against Trichosporon asahii.

This study evaluated the in vitro susceptibility of Trichosporon asahii strains to diphenyl diselenide (DPDS) and ebselen (EBS) alone and in combination with amphotericin B (AMB), fluconazole (FCZ), itraconazole (ITZ) and caspofungin (CAS) using the microdilution method. EBS showed in vitro activity against T asahii strains with minimal inhibitory concentration (MIC) ranged from 0.25 to 8.0 µg/mL. For DPDS, the MIC ranged from 8.0 to 64 µg/mL. The combinations demonstrating the greatest synergism rate against fluconazole-resistant T asahii strains were the following: CAS + DPDS (96.67%), AMB + DPDS (93.33%), FCZ + DPDS (86.67%) and ITZ + DPDS (83.33%). The combinations AMB + DPDS and AMB + EBS exhibited the highest synergism rate against the fluconazole-susceptible (FS) T asahii strains (90%). Antagonism was observed in the following combinations: FCZ + EBS (80%) and FCZ + DPDS (13.33%) against the FS strains, and ITZ + EBS (20%) against the FR strains. Our findings suggest that the antimicrobial activity of DPDS and EBS against T. asahii and its use as an adjuvant therapy with antifungal agents warrant in vivo experimental investigation.

Neuroprotective Benefits of Aerobic Exercise and Organoselenium Dietary Supplementation in Hippocampus of Old Rats.

The progressive decline of neurological functions, such as learning and memory, is an unavoidable consequence of aging. Our previous work suggested that the combination of physical exercise and a diet supplemented with diphenyl diselenide improves age-related memory decline in rats. The present study investigated the effects of physical exercise and a diet supplemented with diphenyl diselenide on the levels of proteins involved in the hippocampal neuroprotection to figure out the mechanisms related to the beneficial effects of this intervention in aged rats. Male Wistar rats (27 months old) were fed daily with standard chow supplemented with 1 ppm of diphenyl diselenide and subjected to swimming training with a workload (1% of body weight, 20 min/day) for 4 weeks. The hippocampus was dissected from the brain and used for the western blot and immunohistochemistry analyses. The results of this study demonstrate that the association of diphenyl diselenide-supplemented diet and swimming exercise increased the levels of proteins involved in neuroprotection and decreased the activation of those related to apoptosis and neuroinflammation in the hippocampus of old rats. This study suggests that physical exercise and a diet supplemented with (PhSe)2 promoted neuroprotection in the hippocampus of aged rats.

Antioxidant effect of quinoline derivatives containing or not selenium: Relationship with antinociceptive action quinolines are antioxidant and antinociceptive.

The present study investigated the antioxidant effect of a new class of quinoline derivatives (a-d) on assays in vitro. Lipid peroxidation, thiol peroxidase-like and free radical scavenging activities were determined to evaluate antioxidant activity of compounds. Thiol oxidase-like and δ-aminolevulinate dehydratase activities were performed as a toxicological parameter. A second objective of this study was to evaluate the in vivo antinociceptive effect of the compound with better antioxidant effect and without toxic effects in a model of nociception induced by formalin in mice. In liver, at 100 µM, compound a reduced the lipid peroxidation to the control levels, while compounds c and d partially reduced it. In brain, only compound d partially reduced the lipid peroxidation at 50 and 100 µM. Compound b did not have an effect on the lipid peroxidation. Thiol peroxidase-like and free radical scavenging activities are not involved in the antioxidant mechanisms of these compounds. Compounds did not present thiol oxidase-like activity and effect on the δ-aminolevulinate dehydratase. In vivo experiments showed that compound a caused an inhibition of licking time in the first and second phases, and edema formation induced by formalin. In conclusion, quinoline derivative without selenium presented better in vitro antioxidant effect and in vivo antinociceptive activity.

Antioxidant effect of quinoline derivatives containing or not selenium: Relationship with antinociceptive action quinolines are antioxidant and antinociceptive

ABSTRACT The present study investigated the antioxidant effect of a new class of quinoline derivatives (a-d) on assays in vitro. Lipid peroxidation, thiol peroxidase-like and free radical scavenging activities were determined to evaluate antioxidant activity of compounds. Thiol oxidase-like and δ-aminolevulinate dehydratase activities were performed as a toxicological parameter. A second objective of this study was to evaluate the in vivo antinociceptive effect of the compound with better antioxidant effect and without toxic effects in a model of nociception induced by formalin in mice. In liver, at 100 µM, compound a reduced the lipid peroxidation to the control levels, while compounds c and d partially reduced it. In brain, only compound d partially reduced the lipid peroxidation at 50 and 100 µM. Compound b did not have an effect on the lipid peroxidation. Thiol peroxidase-like and free radical scavenging activities are not involved in the antioxidant mechanisms of these compounds. Compounds did not present thiol oxidase-like activity and effect on the δ-aminolevulinate dehydratase. In vivo experiments showed that compound a caused an inhibition of licking time in the first and second phases, and edema formation induced by formalin. In conclusion, quinoline derivative without selenium presented better in vitro antioxidant effect and in vivo antinociceptive activity.

Selective inhibition of MAO-A activity results in an antidepressant-like action of 2-benzoyl 4-iodoselenophene in mice.

Depression is a leading cause of disability worldwide. For this reason, the aim of this study was to investigate the possible antidepressant-like activity of 2-benzoyl-4-iodoselenophene (C17H11IOSe), a selenophene compound, in two well-consolidated behavioral assays for screening antidepressant activity (forced swimming test and tail suspension test) in mice. In order to investigate the mechanism of action of C17H11IOSe, it was investigated the activities of cerebral enzymes: monoamine oxidase MAO A and B and Na+, K+ ATPase, and if an inhibitor of serotonin synthesis, p-chlorophenylalanine (pCPA) (100mg/kg) blocks the antidepressant-like effect of C17H11IOSe. Swiss mice received (C17H11IOSe) (5-50mg/kg) or canola oil by the intragastric (i.g.) route before behavioral tests. The results showed that C17H11IOSe at dose range of 5-50mg/kg decreased immobility time in the tail suspension test. In the forced swimming test, C17H11IOSe reduced the immobility time at the doses of 10 and 50mg/kg. C17H11IOSe differently affected the cerebral cortical Na+, K+ ATPase; the effects on this enzyme were dependent of the dose tested. At a dose of 10mg/kg, the compound increased Na+, K+ ATPase activity, while the activity was inhibited at a dose of 50mg/kg. pCPA blocked the antidepressant-like action of C17H11IOSe in mice. Therefore, C17H11IOSe (5-50mg/kg) selectively inhibited MAO-A activity in cerebral cortices of mice. The modulation of serotonergic system contributed to the antidepressant-like action of C17H11IOSe in mice.

Pain-depression dyad induced by reserpine is relieved by p,p'-methoxyl-diphenyl diselenide in rats.

Depression and pain comorbidity represent a neuropsychiatric condition with substantial socioeconomic impact to society. The commonly used antidepressants and analgesics to treat this comorbidity have shown restricted clinical efficacy. In this way, the aim of this study was to investigate the behavioral, biochemical and neurochemical effects of a p,p'-methoxyl-diphenyl diselenide (OMePhSe)2 supplemented diet on pain-depression dyad induced by reserpine in rats. Adult Wistar rats were fed with 10mg (MeOPhSe)2 per kg of rat chow supplemented diet for 30 days. Pain-depression dyad was induced by daily subcutaneous reserpine injection (0.5mg/kg for three consecutive days) from 22 to 24 day of (MeOPhSe)2 supplementation. The results showed that the reserpine injected rats had behavior phenotypes typical of depression-pain dyad and the (MeOPhSe)2-supplemented diet protected against these modifications. Furthermore, the (MeOPhSe)2 dietary supplementation was effective against the increase in the prefrontal cortical MDA levels caused by reserpine. (MeOPhSe)2-supplemented diet triggered a per se augmentation of Nrf-2 levels. The [3H] serotonin uptake, [3H] glutamate uptake and release and MAO activity were not altered in the prefrontal cortices of rats from any experimental group. Therefore, the results indicate that protective effects of a (MeOPhSe)2-supplemented diet can be mediated, at least in part, by its antioxidant property.

A diphenyl diselenide-supplemented diet and swimming exercise promote neuroprotection, reduced cell apoptosis and glial cell activation in the hypothalamus of old rats.

Aging is a process characterized by deterioration of the homeostasis of various physiological systems; although being a process under influence of multiple factors, the mechanisms involved in aging are not well understood. Here we investigated the effect of a (PhSe)2-supplemented diet (1ppm, 4weeks) and swimming exercise (1% of body weight, 20min per day, 4weeks) on proteins related to glial cells activation, apoptosis and neuroprotection in the hypothalamus of old male Wistar rats (27month-old). Old rats had activation of astrocytes and microglia which was demonstrated by the increase in the levels of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba-1) in hypothalamus. A decrease of B-cell lymphoma 2 (Bcl-2) and procaspase-3 levels as well as an increase of the cleaved PARP/full length PARP ratio (poly (ADP-ribose) polymerase, PARP) and the pJNK/JNK ratio (c-Jun N-terminal kinase, JNK) were observed. The levels of mature brain-derived neurotrophic factor (mBDNF), the pAkt/Akt ratio (also known as protein kinase B) and NeuN (neuronal nuclei), a neuron marker, were decreased in the hypothalamus of old rats. Old rats that received a (PhSe)2-supplemented diet and performed swimming exercise had the hypothalamic levels of Iba-1 and GFAP decreased. The combined treatment also increased the levels of Bcl-2 and procaspase-3 and decreased the ratios of cleaved PARP/full length PARP and pJNK/JNK in old rats. The levels of mBDNF and NeuN, but not the pAkt/Akt ratio, were increased by combined treatment. In conclusion, a (PhSe)2-supplemented diet and swimming exercise promoted neuroprotection in the hypothalamus of old rats, reducing apoptosis and glial cell activation.

Swimming exercise and diphenyl diselenide-supplemented diet affect the serum levels of pro- and anti-inflammatory cytokines differently depending on the age of rats.

The increase in the inflammatory process is one of the main factors that contribute to aging. The aim of this study was to investigate the effects of a diphenyl diselenide (PhSe)2-supplemented diet (1p.p.m., 4weeks) and swimming exercise (3% of body weight, 20min per day, 4weeks) on the serum levels of cytokines in Wistar rats of different ages. The results demonstrated an increase in the levels of pro-inflammatory cytokines (IL-1ß, IL-6, TNFα and INFγ) and a decrease in the levels of IL-10, an anti-inflammatory cytokine, with age. In middle-age rats, the swimming exercise and (PhSe)2-supplemented diet decreased serum levels of pro-inflammatory cytokines and increased the levels of IL-10. By contrast, in old rats the swimming exercise protocol increased the serum levels of pro-inflammatory cytokines and decreased the levels IL-10. Diet supplemented with (PhSe)2 did not alter the serum levels of cytokines in old rats. Middle-age and old rats subjected to swimming exercise and supplemented with (PhSe)2 in the diet had a decrease in the serum levels of pro-inflammatory cytokines and an increase in the levels of IL-10. This study demonstrated that swimming exercise and (PhSe)2-supplemented diet affect the serum levels of pro- and anti-inflammatory cytokines differently depending on the age of rats. (PhSe)2 supplemented in the diet had an anti-inflammatory effect, similar to that of induced by swimming exercise, in middle-age rats and reversed the pro-inflammatory effects of swimming exercise in old rats.

Effectiveness of (PhSe)2 in protect against the HgCl2 toxicity.

This work investigated the preventive effect of diphenyl diselenide [(PhSe)2] on renal and hepatic toxicity biomarkers and oxidative parameters in adult mice exposed to mercury chloride (HgCl2). Selenium (Se) and mercury (Hg) determination was also carried out. Mice received a daily oral dose of (PhSe)2 (5.0mg/kg/day) or canola oil for five consecutive days. During the following five days, the animals were treated with a daily subcutaneous dose of HgCl2 (5.0mg/kg/day) or saline (0.9%). Twenty-four hours after the last HgCl2 administration, the animals were sacrificed and biological material was obtained. Concerning toxicity biomarkers, Hg exposure inhibited blood δ-aminolevulinic acid dehydratase (δ-ALA-D), serum alanine aminotransferase (ALT) activity and also increased serum creatinine levels. (PhSe)2 partially prevented blood δ-ALA-D inhibition and totally prevented the serum creatinine increase. Regarding the oxidative parameters, Hg decreased kidney TBARS levels and increased kidney non-protein thiol levels, while (PhSe)2 pre-treatment partially protected the kidney thiol levels increase. Animals exposed to HgCl2 presented Hg content accumulation in blood, kidney and liver. The (PhSe)2 pre-treatment increased Hg accumulation in kidney and decreased in blood. These results show that (PhSe)2 can be efficient in protecting against these toxic effects presented by this Hg exposure model.

Diphenyl diselenide-supplemented diet and swimming exercise enhance novel object recognition memory in old rats.

The benefits of exercise and the element selenium on mental health and cognitive performance are well documented. The purpose of the present study was to investigate whether the intake of a diet supplemented with diphenyl diselenide [(PhSe)2] and the swimming exercise could enhance memory in old Wistar rats. Male Wistar rats (24 months) were fed daily with standard diet chow or standard chow supplemented with 1 ppm of (PhSe)2 during 4 weeks. Animals were submitted to swimming training with a workload (3 % of body weight, 20 min/day for 4 weeks). After 4 weeks, the object recognition test (ORT) and the object location test (OLT) were performed. The results of this study demonstrated that intake of a supplemented diet with (PhSe)2 and swimming exercise was effective in improving short-term and long-term memory as well as spatial learning, increasing the hippocampal levels of phosphorylated cAMP-response element-binding protein (CREB) in old rats. This study also provided evidence that (PhSe)2-supplemented diet facilitated memory of old rats by modulating cAMP levels and stimulating CREB phosphorylation, without altering the levels of Akt.

The impact of a diphenyl diselenide-supplemented diet and aerobic exercise on memory of middle-aged rats.

Selenium is an essential trace element for human health and has received attention for its role as a nutrient. The combination of exercise and nutrients has been proposed to promote health. The aim of this study was to determine the effects of a diet supplemented with diphenyl diselenide (PhSe)2 and swimming exercise on memory of middle-aged rats. Male Wistar rats (12months) received standard diet chow supplemented with 1ppm of (PhSe)2 for 4weeks. Rats were submitted to swimming training (20min per day for 4weeks). After 4weeks, memory was evaluated in the object recognition test (ORT) and in the object location test (OLT). The hippocampal levels of phosphorylated cAMP-response element-binding protein (CREB) were determined. The results of the present study demonstrated that the association of (PhSe)2-supplemented diet and swimming exercise improved short-term memory, long-term memory and spatial learning, and this effect was not related to the increase in hippocampal p-CREB levels in middle-age rats. This study also revealed that middle-aged rats in the swimming exercise group had the best performance in short- and long-term memory. In conclusion, we demonstrated that swimming exercise, (PhSe)2-supplemented diet or the association of these factors improved learning and memory functioning. The hippocampal levels of CREB were not directly related to the benefits of swimming exercise and (PhSe)2-supplemented diet association in memory of middle-aged rats.

Caffeine and diphenyl diselenide improve long-term memory impaired in middle-aged rats.

The aim of the present study was to evaluate the effects of diphenyl diselenide (PhSe)2 supplemented diet (10ppm) associated to the administration of caffeine (15mg/kg; i.g.) for 30days on the novel object recognition memory in middle-aged rats. The present findings showed that (PhSe)2-supplemented diet enhanced short-term memory, but not long-term memory, of middle-aged rats in the novel object recognition task. The (PhSe)2 supplemented diet associated with caffeine administration improved long-term memory, but did not alter short-term memory, impaired in middle-aged rats. Daily caffeine administration to middle-aged rats had no effect on the memory tasks. Diet supplemented with (PhSe)2 plus caffeine administration increased the number of crossings and rearings reduced in middle-aged rats. Caffeine administration plus (PhSe)2 diets were effective in increasing the number of rearings and crossings, respectively, in middle-aged rats, [(3)H] glutamate uptake was reduced in hippocampal slices of rats from (PhSe)2 and caffeine plus (PhSe)2 groups. In addition, animals supplemented with (PhSe)2 showed an increase in the pCREB/CREB ratio whereas pAkt/Akt ratio was not modified. These results suggest that the effects of (PhSe)2 on the short-term memory may be related to its ability to decrease the uptake of glutamate, influencing the increase of CREB phosphorylation. (PhSe)2-supplemented diet associated to the administration of caffeine improved long-term memory impaired in middle-aged rats, an effect independent of CREB and Akt phosphorylation.

Moderate swimming exercise and caffeine supplementation reduce the levels of inflammatory cytokines without causing oxidative stress in tissues of middle-aged rats.

The levels of circulatory inflammatory markers, including interleukin (IL) IL-1ß, IL-6, tumor necrosis factor-α (TNF-α) and interferon (INF-γ), are known to increase associated to aging. Caffeine has been reported to produce many beneficial effects for health. Exercise is considered to be a safe medicine to attenuate inflammation and cellular senescence. The purpose of the present study was to investigate the effects of a moderate-intensity swimming exercise (3 % of body weight, 20 min per day, 4 weeks) and sub-chronic supplementation with caffeine (30 mg/kg, 4 weeks) on the serum cytokine levels in middle-aged (18 months) Wistar rats. The effects of swimming exercise and caffeine on oxidative stress in muscle and liver of middle-aged rats were also investigated. The two-way ANOVA of pro-inflammatory cytokine levels demonstrated a significant exercise x caffeine interaction for IL-1ß (F (1, 16) = 9.5772; p = 0.0069), IL-6 (F (1, 16) = 8.0463; p = 0.0119) and INF-γ (F (1, 16) = 15.078; p = 0.0013). The two-way ANOVA of TNF-α levels revealed a significant exercise × caffeine interaction (F (1, 16) = 9.6881; p = 0.00670). Swimming exercise and caffeine supplementation increased the ratio of reduced glutathione/oxidized glutathione in the rat liver and gastrocnemius muscle. Hepatic and renal markers of damage were not modified. In conclusion, a moderate-intensity swimming exercise protocol and caffeine supplementation induced positive adaptations in modulating cytokine levels without causing oxidative stress in muscle and liver of middle-aged rats.

Antioxidant activity and low toxicity of (E)-1-(1-(methylthio)-1-(selenopheny) hept-1-en-2-yl) pyrrolidin-2-one.

The aim of the present study was to evaluate the potential pharmacological and toxicological properties of (E)-1-(1-(methylthio)-1-(selenopheny) hept-1-en-2-yl) pyrrolidin-2-one (compound 1), an organoselenium compound. In vitro experiments showed that compound 1 presented a reduction in the lipid peroxidation induced by Fe²âº in thiobarbituric acid-reactive species (TBARS) production, and in the generation of reactive species caused by Fe²âº/malonate in DCFH-DA oxidation. The high dose (500 mg/kg) induced an increase on ALT but not on AST activity. Hepatic, but not cerebral, δ-ALA-D activity from mice treated with 500 mg/kg presented a significant inhibition. Brain catalase activity was significantly inhibited by 100 mg/kg whereas hepatic catalase activity showed a significant increase at all doses. Hepatic lipid peroxidation was diminished only at lowest dose (100 mg/kg) whereas for brain tissue, all doses induced a significant reduction in TBARS levels. Brain and liver ascorbic acid contents were increased only at highest dose of compound 1. Urea and creatinine levels were not significantly altered by treatments. This is a promising compound with antioxidant activity and low toxicity, suggesting the potential beneficial activity of compound 1 against oxidative damage in many parameters studied in rats and mice.

Hypolipidaemic activity of orally administered diphenyl diselenide in Triton WR-1339-induced hyperlipidaemia in mice.

OBJECTIVES: A significant association between the trace element selenium and hypercholesterolaemia has been reported. This study was designed to investigate a potential hypolipidaemic effect of diphenyl diselenide ((PhSe)(2)) in Triton WR-1339-induced hyperlipidaemia in mice. METHODS: Triton was administered intraperitoneally (400 mg/kg) to overnight-fasted mice to develop acute hyperlipidaemia. (PhSe)(2) was administered orally (10 mg/kg) 30 min before Triton. At 24 h after Triton injection, blood samples were collected to measure plasma lipid levels. The hepatic thiobarbituric acid reactive substances and ascorbic acid levels as well as catalase and glutathione peroxidase activity were recorded. KEY FINDINGS: (PhSe)(2) administration significantly lowered total cholesterol, non-high-density lipoprotein-cholesterol and triglycerides, whilst it increased high-density lipoprotein-cholesterol levels in plasma of hyperlipidaemic mice. Neither oxidative stress nor the antioxidant effect of (PhSe)(2) was observed in the mouse liver in this experimental protocol. CONCLUSIONS: These findings indicated that (PhSe)(2) was able to lower plasma lipid concentrations. Further studies are needed to elucidate the exact mechanism by which (PhSe)(2) exerted its hypolipidaemic effect in the management of hyperlipidaemia and atherosclerosis.

Convulsant effect of diphenyl diselenide in rats and mice and its relationship to plasma levels.

Diphenyl diselenide [(PhSe)2], an organoselenium compound, presents pharmacological and toxicological properties in rodents. The aim of this study was to carry out the determination and quantification of (PhSe)2 in plasma after oral administration (p.o.) of this compound (500 mg/kg), dissolved in canola oil, in rats and mice. The second objective was to verify the involvement of different routes of administration ((p.o.), intraperitoneal (i.p.) and subcutaneous (s.c.)) and vehicle solutions (canola oil and dimethyl sulfoxide (DMSO)) in the appearance of seizure episodes and in the plasmatic levels of (PhSe)2 in rats and mice. Analysis of (PhSe)2 in blood samples was performed by gas chromatography/flame ionized detector system (GC/FID). Rat and mouse peak plasma (PhSe)2 levels were 13.13 and 10.11 microg/ml (C(max)), respectively, and occurred at 0.5h (T(max)) post-dosing. The use of different administration routes (p.o., i.p. and s.c.) and vehicle solutions (canola oil or DMSO) in rats and mice indicated that the appearance of seizures and (PhSe)2 plasmatic levels are dependent of administration routes (i.p.>p.o.>s.c.), vehicle solutions (DMSO>canola oil) and animal species (mice>rat).

Spinal mechanisms of antinociceptive action caused by diphenyl diselenide.

The present study was designed to investigate further the mechanisms involved in the antinociception caused by diphenyl diselenide in behavioral model of pain in mice. Diphenyl diselenide (1-100 mg/kg), given orally, produced significant inhibition of the biting behavior induced by intrathecal (i.t.) injection of glutamate (175 nmol/site) and N-methyl-d-aspartate (NMDA; 450 pmol/site), with mean ID(50) values of 45.92 (39.74-60.4) and 55.77 (36.52-77.5) mg/kg respectively. However, diphenyl diselenide completely failed to affect the nociception induced by alpha-amino-3-hydroxy-5-mehtyl-4-isoxazolepropionic acid (AMPA; 135 pmol/site), (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD; 50 nmol/site) and kainate (110 pmol/site). This compound also reduced the nociceptive response induced by substance P (SP) (135 ng/site, i.t.), interleukin 1beta (IL-1beta; 1 pg/site), tumor necrosis factor-alpha (TNF-alpha; 0.1 pg/site), bradykinin (BK; 0.1 microg/site) and capsaicin (30 ng/site) with mean ID(50) values of 16.22, 7.06, 6.06, 4.18 and 7.90 mg/kg, respectively. Together, these results indicate that diphenyl diselenide produced antinociception at spinal sites, with a possible interaction with glutamatergic pathways, more specifically via interaction with NMDA receptors, peptidergic or vanilloid systems.

Diphenyl diselenide changes behavior in female pups.

Diphenyl diselenide, (PhSe)(2), is an organoselenium compound that affects a number of neuronal processes. The effect of maternal subcutaneous (s.c.) injection of 25 mg/kg (PhSe)(2) once daily during early postnatal development (from PND 1 to 21) was evaluated in offspring of Wistar rats. The physical and neural reflexes were recorded at pre-weaning period. The behavioral changes in the elevated plus-maze (EPM), open-field and rotarod tasks were performed in 28-day-old pups. Selenium brain status was significantly increased ( approximately 41%) in rat pups. Statistically significant decreases in body weight were observed during lactation period in male and female pups exposed to 25 mg/kg (PhSe)(2). There were no dose-related changes on landmarks indicative of physical and reflexologic parameters of development in rats. (PhSe)(2) induced a disinhibitory effect in EPM behavior according to gender. Specifically, exposure to (PhSe)(2) increased entries and duration in the open arms of the EPM in females but not in males. Locomotor activity and rearing increased by (PhSe)(2) exposure in both male and female offspring in the open field. Both groups were similar in response to motor coordination in the rotarod. We concluded that maternal (PhSe)(2) exposure during lactation increased selenium levels in the pup brain and caused changes on developmental and behavioral parameters of Wistar rat offspring.